Benzocycloheptaisoquinoline derivatives III in producing CNS depressant effects

ABSTRACT

Octahydrobenzo(6,7)- (or (5,6)-) cyclohepta(1,2,3-de)pyrido- (or pyrrolo-) (2,1-a)isoquinolines, and decahydrobenzo(6,7)- (or (5,6)-) cyclohepta(1,2,3-de)-azepino(2,1-a)isoquinolines and derivatives thereof, optionally substituted on the pyrrolidine, piperidine or azepine ring. The compounds are useful CNS depressants, anticonvulsant and antiinflammatory agents, and methods for their preparation and use are also disclosed.

United States Patent 1 Bruderlein et al.

1*Nov. 25, 1975 l BENZOCYCLOHEPTAISOQUINOLINE DERIVATIVES III INPRODUCING CNS DEPRESSANT EFFECTS [75] Inventors: Francois T. Bruderlein,Montreal;

Leslie G. Humber, Dollard des Ormeaux, both of Canada [73] Assignee:Ayerst McKenna and Harrison Ltd., Montreal, Canada Notice: The portionof the term of this patent subsequent to Dec. 10, 1991, has beendisclaimed.

[22] Filed: Sept. 30, 1974 [21] Appl. No.: 510,275

Related U.S. Application Data [60] Division of Ser. No. 242,839, April10, 1972, Pat. No. 3,852,452, which is a continuation-in-part of Ser.No. 97,481, Dec. 2l, 1970, and

a continuationin-part of Ser No. l0,3()6, Feb. 10, 1970, Pat. No.3,657,250.

[52] U.S. Cl. 424/258 [51] Int. Cl A6lk 31/47 [58] Field of Search424/267, 258

Primary ExaminerStanley J. Friedman Attorney, Agent, or Firm lohn P.Floyd [57] ABSTRACT 10 Claims, No Drawings BENZOCYCLOHEPTAISOQUINOLINEDERIVATIVES III IN PRODUCING CNS DEPRESSANT EFFECTS This application isa division of application Ser. No. 242,839, filed Apr. 10, 1972, nowU.S. Pat. No. 3,852,452, issued Dec. 3, 1974, which latter applicationis a continuation-in-part of each of application Ser. No. 97,481, filedDec. 21, 1970, and Ser. No. 10,306, filed Feb. 10, 1970, now U.S. Pat.No. 3,657,250, issued Apr. 18, 1972.

BACKGROUND OF THE INVENTION The present invention relates tobenzocycloheptaisoquinoline derivatives, to intermediates used in theirpreparation, and to processes for preparing these compounds.

The benzocycloheptaisoquinoline derivatives of this invention possessvaluable pharmacologic properties. For example, the compounds exhibituseful central nervous system depressant, anticonvulsant andantiinflammatory properties. Especially noteworthy are the centralnervous system depressant properties of the compounds. Morespecifically, the benzocycloheptaisoquinoline derivatives of thisinvention have a more favourable separation of useful central nervoussystem depressant effects from ataxic properties and undesirableautonomic nervous system effects that are possessed by most other suchdepressants. In addition, the benzocycloheptaisoquinoline derivativespossess a low order of toxicity.

The combination of attributes stated above renders thebenzocycloheptaisoquinolines of this invention useful and desirable astherapeutic agents.

SUMMARY OF THE INVENTION The benzocycloheptaisoquinoline derivatives ofthis invention are represented by formula I or formula Ia,

in which R represents a hydrogen or a lower alkyl and Alk represents theorganic radicals designated A, B, C or D, respectively, in which R R R4R5 R6 R7 R8, R9! R10, R11, 12 13 R14, R15 and R16 are the same ordifferent selected from the group consisting of hydrogen and lower alkylwith the proviso that the carbon atom to which R and R or R and R areattached is bonded to the nitrogen atom of formula I, L represents ahydroxyl or a lower alkanoyloxy; and M is hydrogen, lower alkyl, loweralkenyl, lower alkynyl, a cycloalkyl containing 3 carbon atoms which maybe optionally substituted with a lower alkyl, or a phenyL DETAILS OF THEINVENTION This benzocycloheptaisoquinoline derivatives of this inventionare capable of forming acid addition salts with pharmaceuticallyacceptable acids. Such acid addition salts are included with the scopeof this invention.

The acid addition salts are prepared by reacting the base form of thebenzocycloheptaisoquinoline derivative with either one equivalent orpreferably an excess of the appropriate acid in an organic solvent, suchas ether or an ethanol-ether mixture. Such salts may advantageously beused for the purpose of isolating and- /or purifying the compounds ofthis invention, and may be transformed in a manner known per se into thecorresponding salts with pharmaceutically acceptable acids. These salts,when administered to mammals, possess the same Ipharmacologic activitiesas the corresponding bases. For many purposes it is preferable toadminister the salts rather than the base compounds. Among the acidaddition salts suitable for this purpose are salts such as the sulfate,phosphate, lactate, tartrate, maleate, citrate and hydrochloride. Boththe base compounds and the above acid addition salts have the distinctadvantage of possessing a relatively low order of toxicity.

Also included in this invention are the stereochemical isomers of thecompounds of formulae I and la which result from asymmetric centers,contained therein. These isomeric forms may be prepared by differentmethods and are purified readily by crystallization or chromatography.

Individual optical isomers, which might be separated by fractionalcrystallization of the diastereoisomeric salts formed thereof, forinstance, with dor ltartaric acid or D-(+)-a-bromocamphor sulfonic acid,are also included.

The useful central nervous system depressant activity and theanticonvulsant activity of the benzocycloheptaisoquinoline derivativesof formulae 1 and la and their acid addition salts with pharmaceuticallyacceptable acids may be demonstrated in standard pharmacologic tests,such as, for example, the tests described by R. A. Turner in ScreeningMethods in Pharmacology, Academic Press, New York and London, 1965, pp.99 and 164 172, respectively.

Preferred compounds with central nervous system depressant activityinclude, 1,4,5,6,6a,10,l 1,15boctahydro-3H-benzo[ 6,7 ]cyclohepta[ 1,2,3-de]- pyrido[2,l-a]isoquinoline, S-t-butyl-1,4,5,6,6a,10,11,15b-octahydro-3Hbenzo[6,7]cyclohepta-[1,2,3-de]pyrido[2,1-a]isoquinolin-5-ol,isopropyl-l ,4,5,6,6a, 10,1 1,15b-octahydro-3H-benzo[6,7 ]cyclohepta-[ l,2,3-de]pyrido[2, l -a]isoquinolin- 5-01, and S-t-butyl-l,4,5,6,6a,10,l5,15a-octahydro-3H- benzo[5,6]cyclohepta-[1,2,3-de]pyrido[2,1-a]isoquinolin-5-ol, and particularly the A isomers thereof (see belowfor an explanation of the term, isomer A).

When the benzocycloheptaisoquinoline derivatives of this invention areused as central nervous system depressants for treating psychoses,neuroses or depression or as anticonvulsant agents in mammals, e.g.,rats and mice, they may be used alone or in combination withpharmacologically acceptable carriers, the proportion of which isdetermined by the solubility and chemical nature of the compound, chosenroute of administration and standard biological practice. For example,they may be administered orally in solid form containing such excipientsas starch, milk sugar, certain types of clay and so forth. They may alsobe administered orally in the form of solutions or they may be injectedparenterally. For example, enough saline or glucose to make the solutionisotonic.

The dosage of the present therapeutic agents will vary with the form ofadministration and the particular compound chosen. Furthermore, it willvary with the particular host under treatment. Generally, treatment isinitiated with small dosages substantially less than the optimum dose ofthe compound. Thereafter, the dosage is increased by small incrementsuntil the optimum effect under the circumstances is reached. In general,the compounds of this invention are most desirably administered forcentral nervous system depressant and- The benzocycloheptaisoquinolinederivatives of this invention possess another useful pharmacologicproperty; that is, they are useful an antiinflammatory agents. Moreparticularly, the said compounds of this invention exhibitantiinflammatory activity in standard pharmacologic tests, for example,the tests similar to those described by Robert A. Turner in Screeningmethods in Pharmacology, Academic Press, pp. l52l63, 1965, based on thereduction of pedal inflammation.

When the benzocycloheptaisoquinoline derivatives of this invention areemployed as antiinflammatory agents in mammals, tag, in rats, they maybe administered orally, alone or in tablets combined with pharma-'cologically acceptable excipients, such as starch, milk sugar and soforth. They may also be administered orally in the form of solutions insuitable vehicles such as vegetable oils.

The dosage of the benzocycloheptaisoquinoline derivatives of thisinvention will vary with the particular compound chosen and form ofadministration. Furthermore, it will vary with the particular host undertreatment. Generally, the compounds of this invention are administeredfor antiinflammatory purposes at a concentration level that affordsprotective effects without any deleterious side effects. These effectiveconcentration levels are usually obtained within a therapeutic range of10 mg to 100 mg per kilo per day, with a preferred range of 25 mg to mgper kilo per day.

For the preparation of the benzocycloheptaisoiquinolines of formula I,in which Alk represents organic radical A, B or C, we have found itconvenient to use the process illustrated by FIG. 1 in which R is asdefined above, Alk is organic radical A, B or C, Y represents thehydroxyl group or chlorine, bromine or iodine and X represents thenucleophilic residue derived from a condensing agent used in theBischler-Napieralski reaction such as a bromine or chlorine or aphosphate.

Figure I (Alk organic radical A, B or C) CH NH /or anti-convulsantpurposes at a concentration level that will generally afford effectiveresults without causing any harmful or deleterious side effects andpreferably at a level that is in a range of from about 0.5 mg to about500 mg per kilo per day, although as aforementioned variations willoccur. However, a dosage level that is in the range of from about 5 mgto about mg per kilo per day is most desirably employed in order toachieve effective results.

In practising the above process, 10,1l-dihydro-5H-dibenzo[a,d]cycloheptene-5-methylamine (11), described by L. G. Humberet al., J. Heterocyclic Chem., 3, 247 (1966), is condensed with anappropriate lactone of general formula OAlkC= O in which Alk is organicradical A, B or C, as defined above, to yield the correspondinghydroxyamide of formula 111 in which Y is the hydroxyl group. Theappropriate lactones utilized in this condensation are either availablecommercially, for example, butyrolactone, S-valerolactone, ora-methyl-y-butyrolactone, or they are described with a variety ofmethods for their prepaation in organic chemistry textbooks, such as thetextbook, Methoden der Organischen Chemie," Houben- Weyl, E. Muller,Ed., Vol. VI/2, Georg Thieme Verlag, Stuttgart, 1963, pp. 561-852.

Convenient conditions for this condensation include heating thedibenzocycloheptenemethylamine of formula II and the appropriate lactonetogether at a temperature from 100 to 180C for a period ranging from twoto 24 hours.

Although the condensation may be accomplished without the use ofsolvent, the use of an inert solvent, such as an aromatic hydrocarbon,for example, benzene, or a lower alkanol, for example ethanol, ispreferred. When this condensation is performed in a solvent, then it ispreferable to conduct the reaction at the boiling point of the reactionmixture for a period of seven to 24 hours.

The corresponding hydroxyamide of formula III in which Y is the hydroxylgroup, thus obtained, is subjected to the conditions of theBischler-Napieralski reaction, see for example, W. M. Whaley and T. R.Govindachari in Organic Reactions, 6, 74 (1951). Subsequent heating offthe crude product from this reaction in an inert solvent, preferablybenzene, promotes the completion of the conversion to the quaternarysalt of formula IV in which Alk is organic radical A, B or C and X isdefined as above. Preferred reaction conditions for theBischler-Napieralski reaction include the use of phosphorus oxychlorideas the condensing agent, temperatures ranging from 50 to 150C, areaction time of one to four hours and the use of toluene or benzene assolvent.

Reduction of the quaternary salt of formula IV, obtained as describedabove, with either an alkali metal borohydride, in inert solvents suchas, for instance, methanol or water, or by means of catalyticallyactivated hydrogen, using preferably Raney nickel or palladium orplatinum catalyst, in solvents such as, for example, ethanol, aceticacid or tetrahydrofuran, affords one isomer of the compounds of formulaI in which Alk is organic radical A, B or C and R represents a hydrogenatom. For convenience, this isomer is designated as isomer B and is oneof the configurational isomers, discussed above.

On the other hand reduction of the quaternary salts of formula IV in thepresence of a metal, for example, zinc, with an acid, for example,hydrochloric acid, using an appropriate solvent such as ethanol, affordsanother isomer of the compounds of formula I in which Alk is organicradical A, B or C and R represents a hydrogen atom. For convenience,this isomer is designated as isomer A.

Hence, this present designation of A and B isomers to compounds in thisapplication is used to distinguish between those stereochemical isomershaving different asymmetric centers at the junction of the two ringshaving the nitrogen atom in common.

Furthermore, it is possible to convert either of the isomers A or B orformula I, in which Alk is organic radical A, B or C and R represents ahydrogen atom, into the other. This interconversion is effected byoxidizing either of the above isomers A and B with mercuric acetate orlead tetraacetate, preferably the former; followed by treatment with anappropriate acid of formula HX in which X is as defined above, toregenerate the corresponding quaternary salt of formula IV de- I thedefinition of the acid, HX, used in the above description of theinterconversion of one isomer to the other, may be broadened to includeany nucleophilic residue derived from an acid, for example, perchloricacid or lactic acid, capable of forming a quaternary salt of the classrepresented by formula IV. Such quaternary salts, such as, for example,quaternary salts of formula IV in which X represents a perchlorate orlactate, are then reduced in the aforementioned manner to give thedesired other isomer.

In a variation of the process described above, II III IV- I, thestarting material of formula II is condensed with an appropriatew-haloalkanoic acid halide of formula ZAlkCOZ in which Alk is organicradical A, B or C and Z and Z are the same or different and eachrepresent chlorine, bromine or iodine to yield the correspondinghaloamide of formula III in which Y is a chlorine, bromine or iodine.This condensation is achieved according to the same conditions employedabove for the conversion of the starting material of formula II to thehydroxyamide of formula III in which Y is the hydroxyl group except thatan excess, preferably a three to five molar excess, of a neutralizingagent, for instance, sodium carbonate, is employed to combine with theacid formed as a by-product during the reaction.

The haloamide of formula III thus obtained is then subjected to theconditions of the Bischler-Napieralski reaction, described above, toafford the quaternary salt of formula IV which is reduced to compoundsof formula I in which R is hydrogen and Alk is organic radical A, B or Caccording to methods described above.

The appropriate w-haloalkanoic acid halides used in the precedingprocess are prepared from their corresponding acids by treatment withthionyl chloride, thionyl bromide or phosphorus triiodide. Thecorresponding w-haloalkanoic acids are either commercially available orare described with a variety of methods for their preparation in organicchemistry testbooks, for instance, see description by M. F. Ansell andR. H. Gigg in Rodds Chemistry of Carbon Compounds, Vol. I, part C, S.Coffey, Ed., 2nd. Ed., Elsevier Publishing Co., Amsterdam, 1965, pp.20l2l4.

Alternatively, the above w-haloalkanoic acid halides in which Z and Z,are the same may be readily prepared by treating the lactones of generalformula in which Alk is organic radical A, B or C with thionyl chloride,thionyl bromide or phosphorus triiodide according to the methods such asdescribed in Methoden der Organischen Chemie, I-Iouben-Weyl, E. Muller,Ed., Vol. VI/2, Georg Thieme Verlag, Stuttgart, 1963, pp. 561-852.

Also, the practise of the present process and its variation (see FIG. 1,II III IV I) includes the preparation of thebenzocycloheptaisoquinolines of formula I in which Alk is organicradical A, B or C and R represents a lower alkyl. The latter compoundsare obtained by the action of a lower alkyl magnesium halide on thecorresponding quaternary salt of formula IV according to the conditionsgenerally used for the Grignard reaction. For a description of theseconditions, see L. Fieser The corresponding free acids are eitheravailable comand M. Fieser, Advanced Organic Chemistry, Reinmercially,for example, 4-aminobutyric acid, S-aminohold Publishing Corp., NewYork, 1961, p. 270. Prevaleric acid or 6-aminocaproic acid or aredescribed ferred conditions for this reaction include a temperawith avariety of methods for their preparation in orture range from roomtemperature to the boiling point ganic chemistry textbooks, such as thetextbook, of the mixture, a reaction time from 30 minutes to fourMethoden der Organischen Chemie, Houben-Weyl, hours and the use of etheror tetrahydrofuran as sol- E. Muller, Ed., Vol. XI/2, Georg ThiemeVerlag, Stuttvent. gart, 1958, pp. 269-509.

Alternatively, the quaternary salt of formula IV in Accordingly, thealternate preparation of the quaterwhich Alk is organic radical A, B orC may be prepared nary salt of formula IV, in which Alk and X are asdeby an entirely ifferen process. In this case h r ng fined above, fromanother starting material constitutes material is10,11-dihydro-5H-dibenzo[a,d]cyclohepan alternative process for thepreparation of the bentene-S-carbOXaIdehyde Which IS readily Obtainedzocycloheptaisoquinolines of formula 1, which may be by the action ofthe Grignard reagent prepared from represented schematically by FIG. 2in which R, Alk chloromethyl methyl ether and magnesium, on 10,11- and Xare as defined above.

Figure 2 (M3: organic radical A, B or C) v. LARK VIdihydro-SH-dibenio[a,d]cyclohepten-5-one, described Thebenzocycloheptaisoquinoline derivatives of forby S. O. Winthrop et al.,J. Org. Chem., 27, 230 mula of this invention in which R is hydrogen or(1962). Reductive alkylation of 10,1l-dihydro-5H- lower alkyl and Alk isorganic radical D may be predibenzo[a,d,]cycloheptene-S-carboxaldehydewith an pared by the process illustrated by FIG. 3 in which Rappropriate aminoester of general formula Nl-h-Alk- R R R R", R, R, R, Rand R are as defined COOR in which Alk is organic radical A, B or C inthe first instance.

Figure 3 VII.

I (R ll or lower alkyl and Alk organic radical D) and R" is a loweralkyl, according to the methods de- This process is based in part on thesynthesis of scribed by A. R. Surrey and H. F. Hammer, J. Am.1,2,3,4,6,6a,10,l1,15b-octahydro-5l-l-benzo[6,7]cy- Chem. Soc., 66, 21271944) or A. Skita and w. Stichclohepta-l IPy I q mer, German Patent No.716,668 (Chem. Abstr., 38, (VIII, R R R, R and R H) described previ-2345,l944) for the preparation of derivatives of p- Ously by L. G.Humber et al., Can. J. Chem., 46, 2981 aminobenzoic acid, yields thecyclic amide Vl. Treat- (1968) and by L. G. Humber and M. A. Davis, U.S.ment of the latter compound according to the condi- Pat. No. 3,361,751,issued Jan. 2, 1968. tions of the Bischler-Napieralski reaction,described In P a tising th process represented by FI 3, an above,affords the desired quaternary salt of formula IV acid addition salt,preferably the hydrochloric acid adin which Alk and X are as describedabove, dition salt, of 1,7,8,12b-tetrahydrobenzo[1,2]cy- The appropriateaminoesters used in the preceding l h p -l .4, q described y process areprepared by the usual esterification proce- G. Humber et al., J.Heterocyclic Chem., 3, 247 dures, of their corresponding free acids, seefor exam- (1966), is allowed to react with an unsaturated ketone ple, L.Fieser and M. Fieser, cited above, pp. 370-380. f th rmula R R"C=CRC Cl'R 0 R R, R, R and R are as defined in the first instance, to yield theaminoketone of formula VIII in which R R, R, R R R R, R, R and R are asdefined in the first instance. This extremely facile reaction may beperformed in an inert solvent, for example dimethylformamide,dimethylsulfoxide, dioxane, or lower alkanols, preferably ethanol;however, when using the lower-molecular weight unsaturated ketones, forexample methyl vinyl ketone or ethyl vinyl ketone, it is equallyconvenient to employ an excess of the unsaturated ketone as solvent forthe reaction. Generally, this reaction is performed by heating thecomponents together with or without an inert solvent. Preferredconditions for this reaction include heating the mixture on a steam bathfor prolonged periods of time, for example, from minutes to 4 hours.

Most of the unsaturated ketones used in the preceding reaction areavailable commercially; the remainder are described or may be preparedby general methods cited in organic chemistry textbooks andpublications, see for example, Rodds Chemistry of the Carbon Compounds,Vol. I, part C, S. Coffey, Ed., 2nd ed., Elsevier Publishing Co.,Amsterdam, 1965, pp. 81-91 or D. Beke and C. Szantay, Chem. Ber., 95,2132 1962 If desired, the aminoketone of formula VIII may be separatedinto the A and B isomers by chromatography and purified byrecrystallization.

The aminoketone of general formula VIII may be converted to thebenzocycloheptaisoquinoline derivatives of formula I in which R ishydrogen or lower alkyl and Alk is organic radical D by several methods.Among the preferred methods is the procedure whereby the aminoketone isallowed to react with a lower alkyl, lower alkenyl, lower alkynyl,cycloalkyl containing 3 6 carbon atoms which may be optionallysubstituted with a lower alkyl, or phenyl magnesium halide according tothe conditions of the Grignard reaction, cited above. In this manner,there are obtained the compounds of formula I in which R is hydrogen andAlk is organic radical D wherein R R R,'R and R are as defined in thefirst instance, L is a hydroxyl and M is other than hydrogen as definedin the first instance (in those compounds where M represents acycloalkyl containing 3 6 carbon atoms which is optionally substitutedwith a lower alkyl, said lower alkyl substituent is preferably locatedat the position 1 of the cycloalkyl). The latter compounds may bereadily converted to their corresponding derivatives of formula I inwhich R is a lower alkyl by oxidizing said latter com pounds withmercuric acetate or lead tetracetate, followed by acid treatmentaccording to the first two steps of the procedure described above forconverting either of the isomers A or B of formula I into each other,and treating the resulting, corresponding quaternary salt of formula IVwith a lower alkyl magnesium halide according'to the conditions of theGrignard reaction, cited above.

Alternatively, the aminoketone of formula' VIII may be reacted withappropriate lower alkyl lithium derivatives; cycloalkyl lithiumderivatives, containing 3 6 carbons, which may be optionally substitutedwith a lower alkyl; vinyl lithium; allyl lithium; methallyl lithium;lithium acetylide; l-propynyl lithium; Z-propynyl lithium; or phenyllithium; in an inert solvent by essentially the same technique employedin the Grignard reaction. In this manner, the said aminoketones areconverted to compounds of formula I in which R is hydrogen and Alkis'organic radical D in which R, R R,

V R and R are as defined in the first instance, L is a hydroxyl and M islower alkyl, cycloalkyl containing 3-6 carbon atoms which may beoptionally substituted with a lower alkyl; vinyl, allyl, methallyl,ethynyl, l-

propynyl, 2-propynyl or phenyl, respectively.

It should be noted that the present conversion of aminoketones offormula VIII to the above compounds of formula I may be effected by theaddition of other organoalkali metal reagents. For example, sodium orpotassium acetylide may replace lithium acetylide. However, this use ofother organoalkali metal reagents is most suitable for preparingcompounds of formula I in which Alk is organic radical D in which M is alower 1- alkynyl.

Furthermore, the compounds of formula I in which Alk is organic radicalD in which M is lower alkenyl or alkynyl are readily reduced withhydrogen in the presence of a catalyst to their corresponding loweralkyl derivatives.

Alternatively, the aminoketone of formula VIII may be treated with areducing agent, e.g., an alkali metal borohydride or lithium aluminumhydride, to yield the corresponding compound of formula I in which Alkis organic radical D, wherein L is hydroxyl and M is hydrogen, viz., theS-alcohol described below.

The esterified derivatives of the compounds of formula I in which R ishydrogen or lower alkylandAlk is organic radical D wherein L is a loweralkanoyloxy are obtained by treating the corresponding compounds inwhich L is a hydroxyl, prepared as described above, with the appropriateacid anhydride, at temperatures ranging from 0 C, from 6 48 hours, inthe presence of sodium acetate.

In another aspect of this invention the aminoketone of general formulaVIII may be used conveniently to prepare thosebenzocycloheptaisoquinolines of this invention of formula I in which Ris hydrogen and Allt is organic radical B in which R R, R, R and R areas defined in the first instance, R and R are hydrogen and R is either ahydrogen or a lower alkyl. In other words, the carbonyl of theaminoketone of general formula VIII may either be reduced to amethylene, or a lower alkyl group may be introduced at the carbonyl siteof the aminoketone.

In the first case, where the carbonyl of the aminoketone is reduced to amethylene group, several methods may be employed. These methods includeboth one step reduction, such as the Clemmensen reduction or theWolff-Kishner reduction, or reduction through a reducible intermediatesuch as, for instance, the corresponding derivative of the aminoketoneof formula VIII having a thioketal or tosyloxy group in place of thecarbonyl group. Said derivative having the tosyloxy group is obtained byreduction of the corresponding aminoketone of formula VIII, preferablywith sodium borohydride or lithium aluminum hydride, followed bytosylation of the resulting corresponding 5-alcohol of formula I inwhich R is hydrogen, and Alk is organic radical D wherein R R are asdefined in the first instance, L is hydroxyl, and M is hydrogen. Saidlastnamed 5-alcohol is obtained in two isomeric foams. For a generaldescription of these methods refer to O. H. Wheeler in The Chemistry ofthe Carbonyl Group, S. Patai, Ed., Interscience Publishers, London,1966, pp. 507-566. In practice we have found that an especiallyconvenient manner for reducing the carbonyl group to the methylene groupis to convert-the aminoketone of formula VIII to its correspondingthioketal derivative with ethanedithiol and an acid catalyst, forexample, boron trifluoride etherate. The resulting thioketal de- Figuret (Alk organic radical A, B or C) cum '3 2 2 HZNH- -A1l -Y I'Ia. IIIa.

Illa.

rivative is then reduced with Raney nickel to the de- Likewise, inapplying the process, described above,

sired benzocycloheptaisoquinoline derivative of this dependent on thecompound of formula V as starting invention of formula I in which R ishydrogen and Alk material, the corresponding desired benzocyclohepisorganic radical B in which R R, R, R and R are taisoquinoline of formulala is obtained by approprihydrogen or lower alkyl and R R and R arehydroately chooseing 10,11-dihydro-5l-I-dibenzo-[a,d]cygen.cloheptene-lo-carboxaldehyde (Va) to replace the In the second casewhere a lower alkyl is introduced compound of formula V. In this casethe process is repat the carbonyl site of the aminoketone of generalforresented by FIG. 5 in which R and X are as defined mula VIII, theaminoketone is allowed to react with a hereinbefore and Alk is organicradical A, B or C. lower alkyl magnesium halide or lower alkyl lithiumderivative as described above, followed by dehydration of 8 5 theresulting tertiary carbinol with an acid catalyst, for (Alk organicradical B or c) example, p-toluenesulfonic acid, and then catalytichydrogenation, using the conditions described above, to yield thedesired benzocycloheptaisoquinoline of formula I.

Alternatively, the alkyl group may be introduced at A the site of thecarbonyl group of the aminoketone of --}y formula VIII, by reacting theaminoketone with a lower alkylidenephosphorane according to theconditions of the Wittig reaction; see A. Maercker, Organic Reac- 0tions, 14, 270 (1965), followed by catalytic reduction C of theresulting alkylidene derivative. H H 1 Thus in this second case, thereare obtained the benzocycloheptaisoquinolines of the invention offormula I N Alk in which R is hydrogen and Alk is organic radical B inC/ which R, R R, R, R and R are hydrogen or lower 7 Va. VII.

alkyl and R and R are hydrogen.

For the preparation of the benzocycloheptaisoquinolines of formula la inwhich Alk represents organic rad- Iva. icals A, B, or C, the processesdisclosed herein for the preparation f corresponding b l h The startingmaterial of formula lla may be prepared taisoquinolines of formula I areused with the provision from 10,1 y l fll y p that the tricyclicstarting materials for these processes s rib d by N- J- Leonard et 211-,Amerare chosen with regard to the structural variation re- C m- SOC-,77, 5078 (1 by methods analogous to quired to lead to the desiredcompounds of formula la. Accordingly, in applying one such process,described those used to prepare the compound of formula [1, seel-lumber, et al., (1966 and 1968), cited above, and refabove dependenton the compound of formula II as erences therein, from its correspondingdibenzocystarting material, then the appropriate choice forreclohepten-S-one. A preparation of this starting material placing thestarting material of formula II is 10,11-dihywhich we have foundconvenient is the following:

dro-5l-l-dibenzo-[a,d]cycloheptene-10-methylamine 10,1l-Dihydro-5H-dibenzo[a,d]cyclohepten-l0-one (Ila) in order to preparethe corresponding desired is treated with triethyl phosphonoacetate inthe presbenzocycloheptaisoquinoline of formula Ia. ence of sodiumhydride in tetrahydrofuran according to In other words the process IIIII IV I and its the conditions of the Wittig reaction, see Maercker,variations, described herein for the preparation of the cited above, toafford 10,1l-dihydro-5H-dibenzo[a,dbenzocycloheptaisoquinolines offormula I in which 65 ]cycloheptene-A' -acetic acid methyl ester. Thelat- Alk represents organic radical A, B or C, are utilized ter productis hydrolyzed with potassium hydroxide in with starting material Ilawhereby the preparation of aqueous methanol to give the correspondingacid. The the corresponding benzocycloheptaisoquinolines of acid ishydrogenated in the presence of 10% palladium formula la is achieved inthe manner illustrated by FIG. on carbon in ethanol at room temperatureand 1000 psi 4 in which R, X and Y are as defined hereinbefore and togive 10,1 1-dihydro-5H-dibenzo[a,dlcycloheptene- Alk is organic radicalA, B or C. IO-acetic acid. Subsequent conversion of this latter acid tothe starting material of formula Ila is achieved readily according tothe procedure described by S. N. Alarn and D. B. MacLean, Can. J. Chem.,43, 3433 (1965) for converting 9-xantheneacetic acid to9-xanthenemethylamine.

The starting material of formula Va, utilized above, is prepared readilyfrom 10,1 l-dihydro-5Il-dibenzo[a,d]- cyclohepten-lO-one according tothe procedure disclosed herein for converting 10,1l-dihydro-SH-dibenzo[a,d]cyclohepten-5-one to the compound of formula V.

The benzocycloheptaisoquinolines of formula la in which Alk is organicradical D are prepared by the processes described herein for thepreparation of their corresponding analogs of formula I with theprovision that instead of compound VII, the requisite starting materialis an acid addition salt, preferably the hydrochloric acid additionsalt, of 1,7,12,l2a-tetrahydrobenzo[1,2-]cyclohepta[4,5,6-de]iecquinoline (Vlla). In this case the process isrepresented by FIG. 6 in which R, R, R, R", R R", R, R, R and R are asdefined in the first instance.

The term lower alkanoyloxy as used herein contemplates both straightchain alkanoyloxy radicals containing from two to ten carbon atoms andbranched chain alkanoyloxy radicals containing from four to six carbonatoms and includes acetoxy, propionyloxy, pivaloyloxy, hexanoyloxy andthe like.

The term halo as used herein contemplates halogens and includesfluorine, chlorine, bromine and i0- dine.

The following Examples will illustrate further this invention.

Figure 6 16 of) 1 15 (R z gl m i VIIIa.

is (R1 .1-1 or lower alkyl and Alk Compound Vlla is prepared from thecompound of formula Ila, described above, according to the proceduredescribed by Humber et al., (1966), cited above, for converting 10,11-dihydro-5I-I-dibenzo[a,d]cycloheptene-S-methylamine (II) to thehydrochloric acid addition salt ofl,7,8,l2b-tetrahydrobenzo[1,2]cyclohepta [3 ,4,5] isoquinoline 3,4,5-de] Finally, and if desired, the intermediate aminoketone V VIIIa,obtained in the processes for the preparation of the compounds offormula la in which Alk is organic radical D, is converted to thecorresponding benzocycloheptaisoquinolines of formula la in which R ishydrogen and Alk is organic radical B in which R R R, R and R are asdefined in the first instance, R and R are hydrogen and R is eitherhydrogen or lower alkyl by the procedure described herein for thesimilar conversion the aminoketone of formula VIII to the correspondingbenzocycloheptaisoquinolines of formula I.

The term lower alkyl" as used herein contemplates straight chain alkylradicals containing from one to six carbon atoms and branched chainalkyl radical containing up to four carbon atoms and includes methyl,ethyl, propyl, isopropyl, butyl, isobutyl, and the like.

The term lower alkenyl as used herein contemplates both straight andbranched alkenyl radicals con-. taining from two to six carbon atoms andincludes vicr zmic radical :9)

EXAMPLE 1 10,1 l-Dihydro-5H-dibenzo[a,d]cycloheptene-5- methylamine (8.5g) and y-butyrolactone (3.7 g) are 'heated at C. (internal temperature)for one hour.

After cooling, the solid residue is recrystallized from butyrolactone,a,a-diethyl-, B,B-diethylor ygy-diethyl-y-butyrolactone, a,a-dipropyl-,[3,[3-dipropylor 'y,-y-dipr0pyl-'ybutyrolactone, a,B-dimethyl-,

butyrolactone, oq-methyl-B-ethyl a-ethyl-B-propylor,B-propyl-ymethyl-y-butyrolactone, a,,8,'y-trimethyl-,a-methyl-B-ethyl-y-propyl-, a,a,B,y-tetramethyl-,a,a-dimethyl-B-ethyl-y-propyl,

a,'y-dimethylor B,y-dimethyl-y- 15 a,a,y-trimethyl-B,B-diethylora,a,B,,B,'y-pentamethyl-y-propyl-y-butyrolactone, or 8-valerolactone,a-methyl-, B-methyl-, y-methylor S-methyl-B- valerolactone,

a-ethyl-, B-ethyl-, 'y-ethyl-, or 8-ethyl-8-valerolactone,

a-propyl-, B-propyl-,

valerolactone,

a,a-dimethyl-, B, B-dimethyl-, y,y-dimethylor 5, 8-

dimethyl-S-valerolactone,

a,a-diethyl-., 'y,'y-diethyl-, 'y,'y-diethylor8,8-diethylfi-valerolactone,

a,B-dimethyl-, a,y-dimethyl-, a,8-dimethylor 3,7-

dimethyl-S-valerolactone,

a,B-diethyla,'y-diethyl-, a,6-dipropyl or B,'y-dipropyl-5-valerolactone,

a-ethyl-B-methyl-, or oz-propyl-6-methyl-5-valerolactone,

a,B,-y-trimethylor a,B-dimethyl-y-propyl-8- valerolactone,a,B,'y,8-tetramethyl-, a,B,'y,8-tetraethyl-8-methyl-,

a 1,343,7,'y,8,8-octamethyl-8-valerolactone,

e-caprolactone, a-methyl-, B-methyL, 'y-methyl-, 8-

methylor e-methyl-e-caprolactone,

a,a-dimethyl-, a,'y-diethyl-a-propyl-e-methyl-,

a,'y,8,e-tetraethyl'-, a-propyl-B,e,e-triethyl-y-methyl-,

a,a,/3,B,'y,'y-hexamethylora,a,B,B;y,-y,e-heptamethyl-e-ethyl-e-caprolaetone instead of'y-butyrolactone,

N-[( l0,l l-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)methyl]-4-hydroxy-2-methylbutyramide, -4- hydroxy-3-methylbutyramide,-4-hydroxyvaleramide, m.p. 112-1l3C.,

-4-hydroxy-2-ethylbutyramide,

butyramide,

-4-hydroxy-caproamide, -4-.hydroxy-2-propylbutyramide,

-4-hydroxy-3-propylbutyramide,

tanamide,

-4-hydroxy-2,Z-dimethylbutyramide,

-4-hydroxy-3,3-dimethylbutyramide,

-4-hydroxy-4-methylvaleramide,

-4-hydroxy-2,2-diethylbutyramide,

-4-hydroxy-3,3-diethylbutyramide,

-4-hydroxy-4-ethylcaproamide,

-4-hydroxy-2,2-dipropylbutyramide,

-4-hydroxy-3,3-dipropylbutyramide,

-4-hydroxy-4-propylheptanamide,

-4-hydroxy-2,B-dimethylbutyramide,

-4-hydroxy-2,4-dimethylbutyramide,

-4-hydroxy-3-methylvaleramide,

-4-hydroxy-2-methyl-3-ethylbutyramide,

-4-hydroxy-2-ethyl-3-propylbutyramide,

-4-hydroxy-2-propylvaleramide,

-4-hydroxy-2,3-dimethylvaleramide,

-4-hydroxy-2-methyl-3-ethylheptanamide,

-4-hydroxy-2,2,3-trimethylvaleramide,

-4-hydroxy-2,2-dimethyl-3-ethylheptanamide,

-4-hydroxy-2,2-dimethyl-3,3-diethylvaleramide,

-4-hydroxy-2,2,3,3,4-pentamethylheptanamide, -5- hydroxyvaleramide, mp102C, -5-hydroxy-2- methylvaleramide,

-5-hydroxy-3-methylvaleramide, -5-hydroxy-5- meth-ylvaleramide,

-5-hydroxycaproamide,

-5-hydroxy-2-ethylvaleramide,

valeramide,

y-propylor 6-propyl-8 -4-hydroxy-3-ethyl- -4-hydroxy-hep--5-hydroxy-3-ethyl- 16 -5-hydroxy-4-ethylvaleramide,-5-hydroxy-heptanamide, -5-hydroxy-2-propylvaleramide,-5-hydroxy-3-propylval ramide, -5-hydroxy-4- propyl-valeramide,-5-hydroxyoctanamide, -5-hydr0xy-2,Z-dimethylvaleramide,-5-hydroxy-3,3-dimethylvaleramide, -5-hydroxy-4,4-dimethylvaleramide,-5-hydroxy-5-methylcaproamide, -5-hydroxy-2,2-diethylvaleramide,-5-hydroxy-3,3-diethylvaleramide, -5-hydroxy-4,4-diethylvaleramide,-5-hydroxy-5-ethylheptanamide, -5-hydroxy-2,3-dimethylvaleramide,-5-hydroxy-2,4-dimethylvaleramide, -5-hydroxy-2-methylcaproamide,-5-hydroxy-3,4-dimethylvaleramide, -5-hydroxy-2,3-diethylvaleramide,-5-hydroxy-2,4-diethylvaleramide, -5-hydroxy-2-propyloctanamide,-5-hydroxy-3,4-dipropylvaleramide,-5-hydroxy-2-ethyl-3-methylvaleramide, -5-hydroxy-2-propylcaproamide,-5-hydroxy-2,3,4-trimethylvaleramide, -5-hydroxy-2,3-dimethyloctanamide,-5-hydroxy-2,3,4-trimethylcaproamide,-5-hydroxy-2,3-diethyl-4,4-diethylcaproamide,-5-hydroxy-2,2,3,3,4,4-hexamethylvaleramide,-5-hydroxy-2,2,3,3,4,4-hexamethylcaproamide,-5-hydroxy-2,2,3,3,4,4,5-heptamethylcaproamide, -6-hydroxycaproamide,-6-hydroxy-2-methylcaproamide, -6-hydroxy-3-methylcaproamide,-6-hydroxy-4-methylcaproamide, -6-hydroxy-5-methylcaproamide,-6-hydroxy-heptanamid e, -6-hydroxy-2,2-dimethylcaproamide,-6-hydroxy-2,4-diethyl-2-propylheptanamide,-6-hydr0xy-2,4,5-triethyloctanamide,-6-hydroxy-2-propyl-3,5-diethyl-4-methyloctanamide,-6-hydroxy-2,2,3,3,4,4-hexamethylcaproamide and-6-hydroxy-2,2,3,3,4,4,S-heptamethyloctanamide,

are obtained.

EXAMPLE 2 To a solution of N-[(10,1l-dihydro-SH-dibenzo[a,d]-cyclohepten-5-yl)methyl]-5-hydroxyvaleramide(24.0 g), prepared as described in Example 1, in 400 ml. of toluene isadded phosphorous oxychloride ml) and the reaction mixture is refluxedfor 3 hours. After cooling, dilution with petroleum ether precipitatesan oil. The supernatant layer is decanted and the residual oil isdissolved in benzene. The benzene solution is washed with water, 10%sodium hydroxide solution and then water again, dried and subjected toreflux for 40 minutes to complete the quaternary salt formation. Theresulting precipitate is recrystallized from acetone to give1,3,4,5,6,l0,1 1,15b-octahydrobenzo[6,7]cyclohepta[ l,2,3,-de]pyrido[2,l-

a]isoquinolinium chloride (IV, Alk =CI-I CI-I Cl-I CH and X =Cl), m.p.205207C.

The procedure of Example 2 may be followed to make other quaternarysalts of formula IV. Examples of such quaternary salts are listed inTables I, II and III. In each of these cases an equivalent amount of thestartingj material listed is used instead of N-[ 10,1 l-dihydro-SI-I-dibenzo[a,d]-cyclohepten-5-yl)methyll-S-hydroxyvaleramide used inExample 2. The particular starting materials listed below are describedin Example I.

TABLEI EXAMPLE STARTING MATERIAL (FORMULA III IN WHICH Y =OH AND Alk ISSTRUCTURE LISTED PRODUCT [(PREFIX LISTED BELOW)- l 4 5,9. IO.I4b-HEXAHYDRO- 3I-I-BENZO[6,7]CYCLOHEPTA- TABLE II -Continued PRODUCT[(PREFIX LISTED BELOW)- l,3,4,5,6,10,l l,l5b-OCTAHYDRO- BENZO[6,7]-CYCLOHEPTA[ I .2,3-de]- PYRIDOlZ, l -a]lSOQUINOLINIUM CHLORIDE] 67 2s) 2 s) 2 s)2- CH(CH 6,5.4,4-tetraethyl-3-methyl- 68 C(CH ),C(CH C(CH;,)CH 6,6,5.5,4,4-hexamethyl- 69 C(CH C(CHa)C(CHQ CHCH6,6,5,S,4,4.3-heptamethyl- 70 C(CH;,),C(CH;),C(CH C(CH6,6,5,5,4,4,3,3-octamethyl- TABLE III EXAMPLE STARTING MATERIAL PRODUCT(FORMULA III IN WHICH [(PREFIX LISTED BELOW)- Y OH AND Alk IS1,3,4,5,6,7,l1,12,16b-OCTAHYDRO- STRUCTURE LISTED3H-BENZO[6,7]CYCLOHEPTA[ 1,2,3-de1- BELOW) AZEPINO[2,1-a]lSOQUINOLlNIUMCHLORIDE] 71 CH CH CH CH CH parent quaternary salt,

l,4,5,6,7,l l,l2,l (vb-octahydro- 3H-benzo[6,7]cyclohepta-[l,2,3-de]azepino[2,1'a]isoquinolinium chloride 72 CH(CH )CH CH CH CH7-methyl- 73 CH CH(CH;,)CH CH CH 6-methyl- 74 CH Cl-l,CI-1(CH )CH CHS-methyl- 75 CH,CH CH CH(CH )CH 4-methyl- 76 CH CH CH CH CH(CH 3-methyl-77 C(CH ),CH CH,CH CH 7,7-dimethyl- 73 C(C2H5)(C3H7)CH2CH(C2H5)' CH,CHCH(CH 7,5-diethyl-7-propyl-3-methyl- 79 CH(C H )CH CH(C H )CH- (CH,)CH(C H,,) 7,5,4,3-tetraethyl- 8O CH(C H,)CI-I(C H )CH(CH CH C(C,H7-propyl-6,33-triethyl-5-methyl- 31 3)2 3)2 3)2 CH,CH,7,7,6,6,5.5-hexamethyl- 32 C(CH3)2C(CH3)2C(CH3)2' CH,C(CH=)(C H5)7,7,6,6.5,5,3-heptamethyl-3-ethyl- EXAMPLE 83 To a solution of thequaternary salt,1,4,5,9,10,14bhexahydro-3H-benzo[6,7]cyclohepta[1,2,3-de1pyrrolo[2,1-a]-isoquinoliniumchloride (4.0 g), described in Example 3, in 100 ml of methanol, sodiumborohydride (4.0 g). is added portionwise. The reaction mixture isrefluxed for one hour. After removal of the solvent the residue is takenup in water and extracted with ether. The ether extract is dried andevaporated to dryness. The residue is crystallized from hexane to yield1,3,4,5,5a,9,10,14b-octahydrobenzo[6,7]-cyclohepta[1,2,3-de]pyrrolo[2,1-a]isoquinoline(Isomer B) (I, R H and Alk CH CH CH m.p. 1l2l 13C. The correspondinghydrochloric acid addition salt of this free base has m.p. 3254C.(recrystallized from acetone).

The above isomer B of Example 83 as well as the corresponding Isomer A,may also be prepared by following the procedure of Example 85, seebelow, by using an equivalent amount of quaternary salt noted in Example83 instead of the quaternary salt noted in Example 85. Accordingly,l,3,4,5,5a,9,10,14b-octahydrobenzo[6,7]cyclohepta[1,2,3-de]-pyrrolo[2,1- a]isoquinoline (Isomer A), m.p. 7677C, isobtained. The corresponding hydrochloric acid addition salt of thelatter compound has m.p. 226C.

EXAMPLE 84 The quaternary salt, 1,3,4.5,6,l0,11,15b-octahydrobenzo[6,7]cyclohepta[ 1.2,3-de ]pyrido[2,la]isoquinolinium chloride (1.3 g),described in Example 2, is dissolved in 50 ml. of ethanol and subjectedto hydrogenation at room temperature under atmospheric pressure in thepresence of platinum oxide (50 mg). After a reaction time of two hours,the catalyst is removed by filtration and the filtrate is evaporated todryness. The residue is crystallized from hexane to afford1,4,5,6,6a,10, l l,15b-octahydro-3H-benzo[6,7]cyclohepta[1,2,3-de]pyrido[2,l-a]isoquinoline(Isomer B) (I, R H and Alk CH CI-I,CH CH m.p. 136C. The correspondinghydrochloric acid addition salt of this free base has m.p. 235236C.

EXAMPLE A mixture of the l,3,4,5,6,10,l 1,15boctahydrobenzo [6 ,7]cyclohepta[1 ,2 ,3 -de]pyrido [2,1 a]isoquinolinium chloride (2.0 g) andzinc dust (4.0 g) in 40 ml of concentrated hydrochloric acid and ml ofethanol is heated on a steam bath for one hour. The

alcohol is removed by evaporation and the remainder quaternary salt,

of the mixture is renderedneutral with concentrated ammonia. The mixtureis then extracted with benzene.

cloheptaisoquinoline derivatives of formula I in which R is a hydrogen.In each case an equivalent amount of appropriate starting material, aquaternary salt of formula IV to give the desired product is used inplace of the quaternary salts noted in Examples 83, 84 and 85. Examplesof such benzocycloheptaisoquinoline derivatives which may be prepared bythese procedures are listed in Tables IV, V and VI with a notationreferring to the source of the appropriate starting material.

TABLE IV EXAMPLE NUMBER OF EXAMPLE PRODUCT DESCRIBING [(PREFIX LISTEDBELOW)- QUATERNARY SALT STARTING I,3,4,5a,9,I0,I4b-OCTAHYDRO- MATERIALBENZO[6,7]CYCLOHEPTA[1,2,3-del- PYRROLO[2,I-a]ISOQUINOLINE] 86 4S-methyl- 87 5 4-methyl 88 6 3-methyl [Isomer B has the followingcharacteristics in its nmr spectrum (CDCI ):87.8 (H), 7.4-6.65(6H), 4.49(H). 3.3-1.6 (12 H), [.38 (CH,)] 89 7 S-ethyl- 90 8 4-ethyl- 9l 93-ethyl- 92 I -propyl- 93 II 4-propyl 94 I2 3-propyl- 95 I3 5,S-dimethyl- 96 I4 4,4-dimethyl- 97 I5 3,3-dimethyl- 98 I6 5,5-diethyl-99 I 7 4,4-diethyl- I00 I8 3,3-diethyll0] l9 5,5-dipropyl- I024,4-dipropyl- I03 21 3,3-dipr0pyl- I04 22 5,4-dimethyl- I05 235,3-dimethyl I06 24 4,3-dimethyl- I 07 25 5 -methyl-4-ethyl- I08 265-ethyI-4-propyl- I09 27 4propyI-3-methyl- I I0 28 5,4,3-trirnethyl- I II 29 5-methyI-4-ethyI-3-propyl- I I2 30 5,5,4,3-tetramethyl- I I 3 315,5-dimethyl-4-ethyI-3-propyl- I I4 32 5,5,3-trimethyI-4,4-diethyl- II533 5,5,4.4,3-pentamethyI-3-propyl- TABLE V PRODUCT DESCRIBING [(PREFIXLISTED BELOW)- QUATERNARY SALT STARTING I,4,5,6,6a,I0,I 1,15b-OCTAHYDRO-MATERIAL 3H-BENZO[6,7]CYCLOHEPTA[1,2,3-de1- PYRIDOl2,I-a]ISOQUINOLINE] II6 34 6-methyl- I I7 35 SmethyI- I18 36 4-methyl- I19 37 3-methyl- I2038 6-ethyl- I2I 39 S-ethyl- I22 40 4-ethyl- I23 41 3-ethyl- I 24 426-propyl- I25 43 S-propyl- I26 44 4-propyl- I27 45 3-propyl- I 28 466,6-dimethyl- I29 47 5,5-dimethyl- I30 48 4,4-dimethyl- I 3 I 493,3-dimethyl- I32 50 6,6-diethyl- I33 51 5,5-diethyl- I 34 5 24,4-diethyl- I35 53 3,3-diethyl- I36 54 6,5-dimethyl- I37 556,4-dimethyl- I38 56 6,3-dimethyI- I39 57 5,3-dimethyl- I40 586.5-diethyl- I41 59 6,4-diethyl- I42 60 6,3-dipropyl- I43 6I6.3-dipropyl- EXAMPLE NUMBER OF EXAMPLE DESCRIBING PRODUCT [(PREFIXLISTED BELOW QUATERNARY SALT STARTING l,4.5.6,6a,l0,l 1,1 Sb-OCTAHYDRO-MATERIAL 3H-BENZO[6,7]CYCLOHEPTAI l,2,3-de]- PYRIDOlZ,I-allSOOUlNOLINE]144 62 G-ethyI-S-methyl- I45 63 6-propyl-3-methyl- 146 646.5,4-trimethyl- I47 65 6,5-dimethyl-3-propyl- I48 666,5,4,3-tctramethyl- 149 67 6,5,4,4-tetraethyl-3-methyl- 150 686,6,5,5,4,4-hexamethyl- I51 69 6,6,5.S,4.4,3-heptamethyl- 152 706,6,5,5,4,4,3,3-octamethyl- TABLE VI EXAMPLE NUMBER OF EXAMPLE PRODUCTDESCRIBING [(PREFIX LISTED BELOW)- QUATERNARY SALT STARTINGl,3,4,5,6,7,7a,l1,12,16b-DECAHYDRO- MATERIALBENZO[6,7]CYCLOHEPTA[1,2,3de]- AZEPINO[2,l-a]lSOQUINOLINE] 153 71 parentbase 1,3,4,5,6,7,7a,11,12,16b-

decahydrobenzo[6,7]cycloheptal1,2,3-de]- azepino[2,1-a]isoquinoline 15472 7-methyl- 155 73 6-methyl- 156 74 S-methyl- 1S 7 7 5 4-methyl- I58 76B-methyl- 159 77 7,7-dimethyl- 160 78 7,5-diethyI-7-propyl-3-methyl- 16179 7,5,4,3-tetraethyl- 162 80 7-propyl-6,3,3-triethyI-5-methyl- I63 817,7,6,6,5,5-hexamethyl- 164 82 7,7,6,6,5,5,3-heptamethyl-3-ethyl-EXAMPLE 165 To a warm solution of the benzocycloheptaisoquinoline,1,4,5,6,6a,10,11,15b-octohydr-3H-benzo[6,7-]cyclohepta[1,2,3-de]pyrido[2,1-a]isoquinoline (lsomer B) (0.7 g),described in Example 84, in 18 ml of water, 4 ml of acetic acid and mlof tetrahydrofuran, mercuric acetate (3.08 g) is added portionwise. Themixture is boiled for one hour. Solid mercurous acetate is collected ona filter and the filtrate is rendered alkaline with aqueous sodiumhydroxide and extracted with ether. The ether extract is dried, and thentreated with gaseous hydrochloric acid. The resulting precipitate iscollected and recrystallized from acetone to afford a product identicalto 1,3,4,5,6,10,1 1,15b-octahydrobenzo[6,7]cyclohepta1[1,2,3-de]pyrido[2,1- a]isoquinolinium chloride obtained in Example 2.

The same product is isolated when the corresponding Isomer A, describedin Example 85, instead of above Isomer B, is used as the startingmaterial.

In the same manner, but using any of the benzocycloheptaisoquinolineslisted in Examples 83, 86 to 164 and 189 to 292, see below, instead ofthe benzocycloheptaisoquinoline of this Example, the correspondingquaternary salts of formula IV are obtained.

EXAMPLE 166 A mixture of 10,1l-dihydro-5l-l-dibenzo[a,d]cycloheptene-S-methylamine (20.0 g),S-chlorovaleric acid chloride (19.2 g) and sodium carbonate (35.0 g) in250 ml of benzene is stirred and subjected to reflux for 16 hours. Thereaction mixture is diluted with water. The benzene layer is separatedand washed with water, dried and evaporated to dryness. The residue iscrystallized from benzene-hexane to afford the haloamide N-[( 10,11-dihydro-5H-dibenzo[a,d]cyclohepten- 5-yl)methyl]-5-chlorovaleramide(Ill, Alk CH CI-I CH CH and Y Cl),'m.p, 98-99C.

The procedure of Example 166 may be followed to make other haloamides ofthis invention of formula III in which Alk is as defined above and Y isa chlorine by using an appropriate w-haloalkanoic acid halide, describedabove, instead of 5-chlorovaleric acid chloride.

The above N-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-S-yl)methyl]-5-chlorovaleramide,and the other haloamides of this invention may be converted to thecorresponding quaternary salts of formula IV of this invention forexample, the quaternary salts described in Examples 2 to 82, bysubjecting said haloamides to the conditions of the Bischler-Napieralskireaction, for example, the conditions described in the procedure ofExample 2.

EXAMPLE 167 A solution of chloromethyl methyl ether (40.2 g, 0.5 mole,freshly distilled) in dry tetrahydrofuran ml) is prepared, and about 5ml of that solution are added to a stirred mixture of magnesium turnings(12.0 g, 0.5

g atom) and mercuric chloride (500 mg) in tetrahydrofuran (20 ml) untilan exothermic reaction ensues. The flask is cooled to 0 10 and theremainder of the chloromethyl methyl ether solution is added dropwisewith thorough agitation. After completion of addition a solution of 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-S-one (56.1 g 0.25 mole) intetrahydrofuran is- EXAMPLE 168 A solution of 10,1l-dihydro-S-methoxymethyl-SH- dibenzo[a,d]cyclohepten--ol (52.0 g 0.21mole) and formic acid (60 ml) is heated under refluxing conditions forthree hours, The mixture is cooled, diluted with water (500 ml) and theoil is extracted into benzene. Evaporation of the solvent yields thecrude aldehyde as a viscous oil.

The product is stirred overnight at room temperature with a solution ofGirard-T" reagent (40 g) in methanol (400 ml). The precipitate iscombined with the residue obtained on evaporation of the methanol. TheGirard adduct is dissolved in water and the solution is extracted withether (6 X 100 ml) to remove non-carbonylic impurities. Hydrolysis ofthe adduct is effected by stirring the aqueous solution overnight (25)with 40% sulfuric acid. The precipitated product is filtered off, washedwell with water and dried to yield 10,1l-dihydro-SH-dibenzo[a,d]-cycloheptene-S-carboxaldehyde as a solid withrn.p. 76-77C which may be purified by distillation (hp. l35=l38C/0.2 0.3mm) or recrystalliaation from cyclohexane to m.p. 78C., 'y ,,"'="s: 2700(GB stretching); 1720 cm (CHO).

The compound is also characterized as the 2,4-dinitrophenylhydrazone,mp. 217C (from acetic acid) 'y 't 3300 (NH); 1610 (C N);1315,1510 cm 2)-EXAMPLE 169 By subjecting a mixture of10,1l-dihydro-5H-dibenzo=[a,d]cycloheptene-Scarboxaldehyde (2.2 a).described in Example 168, and S-aminovaleric acid ethyl ester (1.45 g)and zinc dust (3.0 g) in 3.0 ml of acetic acid and 100 ml of benzene, toa two hour reflux, followed by removal of the excess also by filtration,addition of dilute sodium hydroxide solution to render the mixturealkaline and extraction with benzene affords the cyclic amide,N-[(10,11dihydro-SH-dibenzo[ a,d-]cyclohepten=5=y1)methyl]=2=piperidone,

'y 1650 arm, as an oil. Further treatment of this oil according to theconditions of the Bischler- Napieralski reaction describedin Example 2,yields a product identical with the quaternary salt, 1,3,4,5,6,10,11,15b=octahydrobenzo[6,7]cyclohepta[1,2,3=de]pyrido[2,l=alisoquinoliniumchloride obtained in Example 2.

The procedure of Example 169 may be followed to make other quaternarysalts of formula IV, for exam =ple, the quaternary salts described inExamples 3 to 82.

In each case an equivalent amount of the appropriate amino ester ofgeneral formula NH =Alk=COOR", in which Alk is organic radical A, B or Cand R" is a lower alkyl, is used instead of 5=aminovaleric acid ethylester.

EXAMPLE 170 The quaternary salt, 1,3,4,5,6,10,11,1Sb=octahy=droben2o[6,7]cyclohepta[1 ,2,3=de]pyrido[2,1= alisoquinolinium chloride(0.001 mole), described in Example 2, is added portionwise to the alkylmagne= slum halide, methyl magnesium iodide (0.002 mole) in 100 ml ofether. The reaction mixture is refluxed for 40 minutes, Excess methylmagnesium iodide is destroyed 26 by the slow addition of a saturatedsolution of ammonium chloride. The ether layer is separated, dried andconcentrated to dryness. The residue is subjcctd to chromatography onalumina (activity-l Elution with benzene gives6a-methyl-l,4,5,6,6a,10,l1,15b-0ctahydro-3l-i-benzo[6,7] l,2,3-de]pyrido[2,1-a]isoquinoline (I, R CH and Alk CH CH CH CH m.p.l19120C, after recrystallization from hexane. This correspondinghydrochloride acid addition salt of this benzocycioheptaisoquinolinederivative has mp. 270C (dec.) after recrystallization frommethanolether.

The procedure of Example 170 may be followed to prepare the remainingbenzocycloheptaisoquinoline derivatives of this invention of formula Iin which R represents a lower alkyl, by using the appropriate quaternarysalt of formula IV, for example the quaternary salts described inExamples 2 to 82, and 165 together with the appropriate lower alkylmagnesium halide. For example, in this manner the 6a-methyl-, 6a-ethyland 6a-propyl analogs of the benzocycloheptaisoquinoline derivativesdescribed in Examples 83 164 are obtained by using the same quaternarysalt starting material employed in the those Examples together with thealkyl magnesium halides, methyl, ethyl or propyl magnesium bromide,respectively.

EXAMPLE 171 To freshly distilled l-buten-3-one (5.4 g),1,7,8,l2btetrahydrobenzo[ 1,2 ]cyclohepta[ 3,4,5-de1isoquinolinehydrochloride (5.4 g) is added portionwise. The mixture is heated on asteam bath for 30 minutes, becoming homogenous and finally semi-solid.The mixture is diluted with ether and the resulting precipitate iscollected on a filter and washed with ether. The precipitate isdissolved in 10% aqueous sodium hydroxide and extracted with ethylacetate. The extract is dried and evaporated to dryness. The residue iscrystallized from acetone-hexane to afford 1,3,4,6,6a,10,11,15b-octahydro-5H-benzo[6,7]cyclohepta[ 1 ,2,3-de]pyrido[2,1-a]isoquinolin-5-one, (V111, R R, R", R and R H), m.p. =155C. Thisproduct is a mixture of the A and B isomers, which may be separated bychromatography on silica gel. Elution with 2 0% chloroform in benzenegives 1 ,3,4,6,6a,10,1 1,15b-octahydro-5H-benzo[6,7]-cyclohepta[ l,2,3-de]pyrido[2,1-a]isoquinolin- S-one (isomer B), m.p. 202=203C afterrecrystallization from acetone-hexane. Elution with chloroform gives thecorresponding isomer A, m.p. 163-165C, after recrystallization fromacetone-hexane.

The procedure of Example 171 may be used to prepare other aminoketonesof formula Vlll. In each case an equivalent amount of an appropriateunsaturated ketone of formula in which R, R, R", R and R are as definedin the first instance, is used instead of l-buten=3=one. Exam= ples ofsuch aminoketones are listed in Table Vll to= gether with theappropriate unsaturated ketones used as starting materials,

TABLE VII STARTING MATERIAL AMINO KETONE PRODUCT (FORMULA VIII) [(Prefixlisted below) I] 1,3,4,6,6a,10,1 1,1Sb-OCTAHYDRO- Example R R C CRC-CHR'R" 5H-BENZO[6,7]-CYCLOHEPTA[1,2,3-

de]PYRlDO[2,l-al-lSOQUlNOLlN- Rll R13 RH R15 RIB 172 CH H H H H3-methyl- 173 H H CH H H 4-methyl- 174 H H H CH H6-methyl-;(m.p.181183C) 175 C H H H H H S-ethyl- 176 H H C H H H4-ethyl- 177 H H H C H H 6-ethyl- 178 nC H-, H H H H 3-propyl- 179 H HnC H-, H H 4-propyl- 180 H H H nC H, H 6-propyl- 181 CH; CH: H H H3,3-dimethyl-;(m.p.185-192C) 2 H H H CH CH 6,6-dimethyl- 18 183 H H H CH C H 6,6-diethyl- 184 CH H H C H H 6-ethyl-3-methyl- 185 CH CH H Hn-C;,H 3,3-dimethyl-6-propyl- 186 CH;, CH; CH CH CH 3,3,4,6,6-pentamethyl- 187 H H secC H-, H H 4-sec-butyl-;(m.p. l44148C) 188CH;, H CH H H 3,4-dimethyl-;(m.p.239242C) EXAMPLE 189 A solution of theaminoketone, 1,3,4,6,6a,10,11,15boctahydro-5H-benzo[6,7 ]cyclohepta[l,2,3-de]- pyrido[2,l-a]is0quinolin-5-one (lsomer A), (2.0 g), describedin Example 171, in 100 ml of tetrahydrofuran is added to a solution ofthe Grignard reagent, ethyl magnesium iodide, prepared from 0.8 g ofmagnesium and 5.2 g of ethyl iodide in ether. The reaction mixture issubjected to reflux for half an hour and the excess of the Grignardreagent is destroyed with water. The reaction mixture is extracted withether. The ether extract is dried and then evaporated to dryness toyield an oily residue. The residue is purified by chromatography onalumina. Elution with benzene-acetone affords the free base, S-ethyl-l,4,5,6,6a, l 0,1 1,15b-octahydro-3H-benzo[6,7 ]-cyclohepta[l,2,3-de]pyrido[2, 1 -a]isoquinolin- 5-01, (lsomer A) (l, R H and Alk CHCH C(C H )(OH)CH 3400 cm (broad). The corresponding hydrochloric acidaddition salt of this product has m.p. 263C (dec.).

In the same manner but using the B isomer instead of the A isomer of1,3,4,6,6a,l0,11,15b-octahydro-5H-benzo[6,7]cyclohepta[1,2,3-de]pyrido-[2,1- a]isoquinolin-S-one,described in Example 171, the B isomer of 5-ethyl-1,4,5,6,6a,10,11,15b-octahydro-3H- benzo[6,7]-cyclohepta[l,2,3-de]pyrido[2,la]isoquinolin-S-ol, nmr (CDCL -,)84.52 (d,1H); thecorresponding hydrochloric acid addition salt of this isomer has m.p.245-249C.

EXAMPLE 190 To ml of a commercial molar solution of the lithiumderivative, t-butyllithium, (0.03M) in pentane,1,3,4,6,6a,10,1l,15b-octahydro-5H-benzo[6,7]cyclohepta[ 1,2,3-de]pyrido[ 2, l -a]isoquinolin-5-one (lsomer A), (3.0g.,0.01M)dissolved in 50 m1. of benzene is added dropwise with stirring andcooling. After stirring at room temperature for 2.5 hr., the reactionmixture is decomposed with water. The organic layer is separated, driedover magnesium sulfate and concentrated to give an oil. The oil isdissolved in benzene and subjected to chromagraphy on a column of basicalumina (activity =11). Elution of the column with chloroform-benzene(1:1) gives S-t-butyl- 1,4,5,6,6a,10,11,15b-octahydro-3H-benzo[6,7]cyclohepta[1,2,3-de]pyrido[2,1-a]is0quinolin-5-ol (lsomer A), nmr(CDCl )64.87(t,lH). The corresponding hydrochloric acid addition salt of thiscompound has m.p. 305-310C.

1n the same manner but using the B isomer instead of the A isomer ofl,3,4,6,6a,l0,l1,15b-octahydro-5H- benzo[6,7 ]cyclohepta[l,2,3-de]pyrido[2, l a]isoquinolin-S-one, described in Example 171, theB isomer of the product of this Example is obtained.

EXAMPLE 191 A solution of 1,3,4,6,6a,10,,1 l,l5b-0ctahydro-5H-benzo[6,7]cyclohepta[1,2,3-de]pyrido[2,la]isoquinolin-S-one (lsomer A)(3.0g), described in Example 171, in tetrahydrofuran ml) is addeddropwise to a suspension of sodium acetylide in liquid ammonia, preparedfrom 2.5 g of sodium in 200 ml of ammonia by bubbling acetylene inpresence of ferric nitrate as catalyst. The reaction mixture is stirredfor 3 hours in a dry ice-acetone bath, then 5 g of ammonium chloride isadded and the ammonia is allowed to evaporate at room temperature. Wateris added and the residue is extracted with ethyl acetate. The extract isdried over magnesium sulfate, and evaporated to dryness. The residue iscrystallized from hexane to give S-ethynyl-l ,4,5,6,6a,l0,11,15b-octahydro-3H-benzo[6,- 7]ocyclohepta[ l,2,3-de]pyrido[2,1-a]isoquinolin-5-ol (lsomer A)(I,R H and Alk CH CHC(C=CH)(CH)CH2), m.p. -l66C. The corresponding hydrochloride salt hasm.p. 280-282C.

In the same manner but using the B isomer instead of the A isomer of1,3,4,6,6a,l0,1 1,15b-octahydro-5H-benzo[6,7]cyclohepta[1,2,3-de]pyrido[2,la]isoquinolin-S-one, describedin Example 171, the B isomer of the product of this Example is obtained,m.p. 176-178C.

An equivalent amount of potassium acetylide, prepared from potassiuminstead of sodium, and acetylene, as described above, may replace thesodium acetylide in the procedure of this Example.

EXAMPLE 192 A solution of S-ethynyl-l ,4,5,6,6a,10,l 1,15b-octahydro-3H-benzo[6,7 ]cyclohepta[ l ,2,3-de ]pyrido[2,1-a]isoquinolin-S-ol, (lsomer A), described in Example 191, is subjectedto hydrogenation using platinum as a catalyst according to the procedureof Example 84. In

this manner, -ethyl-l,4,5,6,6a,l0,l l,l5b-octahydro- 3H-benzo[ 6,7]cyclohepta[ 1,2,3-de ]pyrido[2, I

a]isoquinolin-5-ol (Isomer A), nmr(CDCl )84.88 the Example.

' TABLE VII'I Example Grignard Reagent Product [(Prefix nmr of product,m.p. of corresor Lithium Derilisted below)- 8 (CDCI ponding hydrovative,starting l,4,5,6,6a,l0, chloric acid material l 1,1 Sb-octahydroadditionsalt,

' 3H-benzo[6,7]- "C.

cycloheptal l '.2,3- de]pyrido[2,l-a]- isoquinolin-S-ol] I93 nC,H,,LiS-butyl- 4.90 (t,lH) 287-289 194 CH =CHCH MgBr 5-allyl- 4.70 (t,lH)280-282 195 (CHQQCHMgCI S-isopropyl- 4.90 (t,lH) 282-284 196 CH MgClS-methyl- 4.92 (t,lK) 254-256 1 197 (CH CHLi 5-cyclopropyl- 4.92 (LIH)260-262 198 CH;,C CLi 5-( l-propynyl)- 4.54 (L1H) 199 n C H Li S-propyl-4.87 (LIH) 290-29! 200 nC H Li 5-hexyl- 4.89 (t,lH) Y 285-287 201 -Li5-phenyl- 4.92 (t,lH) 290-292 h 202 (CH CHLi S-cyclohexyl- 4.92 (t,lH)312-314 203 CH CHLi 5-vinyl- 4.90 (t,lH)

(t,lH), an isomer of the product of the same name obtained in Example189 with respect to the configuration of the S-hydroxyl. Thecorresponding hydrochloride salt of this present isomer has m.p.2l22l4C.

In the same manner but using the B isomer instead of the A isomerof5-ethynyl-l ,4,5,6,6a,l0,l 1,15b-octahydro-3I-I-benzo[ 6,7]cyc1ohepta[ l ,2,3-de ]pyrido[ 2, 1 a]isoquinolin-5-ol, described inExample 191, there is obtained the B isomer of 5-ethyl-l,4,5,6,6a,l0,l1,15boctahydro-3H-benzo[6,7]cyc1ohepta-[1,2,3-de1- pyrido 2, l-a]isoquinolin-5 -ol, nmr(CDCL )84.52(d,lI-I), which is an'isorner ofthe product of the same name obtained in Example 189 with rspect to theconfiguration of the S-hydroxyl.

The procedure of Examples 189 or 190 may be used to prepare other5-substituted derivatives of The corresponding B isomers of the productsof Examples I93-203 are obtained in the same manner as the A isomers ofthese Examples by using the B isomer instead of the A isomer of thestarting aminoketone of Example I89.

The procedure of Example 189 may be used to prepare S-ethyl derivativesof formula I in which R is hydrogen and" Alk is organic radical D inwhich R, R ,R, R and R are each hydrogen or lower alkyl, L is hydroxyand M is ethyl. Examples of such 5-ethyl derivatives are listed below inTable IX. In each case an equivalent amount of the corresponding,starting aminoketone, noted-by the Example in which it is prepared, isused instead of l,3,4,6,6a,10,1l,l5b-octahydro-5'H-benz0[6,7]cyclohepta[ l ,2,3-de ]pyrido[ 2, 1 -a] isoquinolin-S-one.

The procedure of Examples 189 or 190 may be folclohepta[l,2,3-de]pyrido[d,l-a]isoquinolin-5-ol, comlowed to prepare other5-substituted derivatives of formula I in which R is hydrogen and Alk isorganic radical D in which R", R, R" and R are each hydrogen or loweralkyl, L is hydroxy and M is as defined in the first instance. Examplesof such 5-substituted derivatives are listed in Table X together withthe appropriate starting aminoketone which is noted by the Example -inwhich the starting aminoketone is prepared. Also, noted therein is theappropriate Grignard rea- 32 a]isoquinolin-5-ol; nmr 8 (CDCI 5.00(m,lH),is obtained by using the aminoketone of Example 187 and the lithiumderivative, isopropyllithium, in the case of using the procedure ofExample 190 as described 5 above. The corresponding hydrochloric acidaddition salt of this product has m.p. 250-256C.

TABLE X Grignard reagent or lithium derivative, starting materialExample No. of the Example in which the starting aminoketone is preparedCH CHL' 2): l

CH CHCH Li HC 5 CU 22 HLi C H Mgl CH C(CHQCH Mg Cl HC 5 CCH Li CH CCHL'- 2):: a) l 5-ethyl-3-methyl- 3-methyl-5-( Z-mcthallyl 3-methyl-5-(l-propynyl) 5-cyclobutyl-3-methyl- 3-methyl-5-(1-methylcyclohcxyl)-3-methyl-5-phenyl- 4-methyl-5-propyl- 4-methyl-5-vinyl-4-methyl-5(2-propynyl)- 5-cyclopentyl-4-methyl- 4-methyl-5-phenyl-5-allyl-6-methyl- 5ethynyl-6-methyl- 3-ethyl-5-( 1-propy1cyclobutyl)3-ethyl-5-phenyl 4.5-diethyl- 4-ethyl-5-(2-methallyl)-4-ethyl5-(2-propynyl)- 6-ethyl-5-( l-methylcyclop ropyh- 3,5-dipropyl-5-allyl-3 propyl- S-cyclopentyl-S-propyl- 5-(1-ethylcyclopentyl)-3-propyl- TABLE X-continued Example No. of theGrignard reagent or Product [(Prefix listed below Example in lithiumderivative, l,4.5.6,6a,l0,l l,l5b-octahydro which the starting material3H-benzo[6,7]cyclohepta[ l,2,3- startingdelpyridoI2,l-a]isoquinolinaminoketone 5-01] is prepared l' l 285 188(CH CHLl S-cyclopropyl3,4dimethylr| 286 188 (CH C(CH )Li3,4-dimethyl-5-( l-methylcyclo- LA propyl)- 4 287 171 (CH CHL1S-cyclobutyl- 288 Hi (CH C(nC;,H-,)Lr 5-( l-propylcyclopropyl)- l 289171 (CH C(C H )L| 5-( l-ethylcyclobutyl)- 1 290 171 (CH ),C(CH;.,)L1 5-(l-methylcyclopentyl)- 1 291 171 (CH,) C(CH;,)L|- 5( l-methylcyclohexyl)-l' l 292 171 (CH C(Cl-l,-,)Li S-( l-methylcyclopropyl)- Prepared fromthe corresponding bromide deriviatives according to the method of R. G.Jones and H. Gilman. Organic Reactions, 6. 352 (1951). The correspondingcyclobutyl. cyclopentyl and cyclohexyl bromides are prepared by themethod of]. G. Traynham and O. S. Pascual, J. Org. Chem., 21, 13621956); the corresponding cyclopropyl bromides are prepared by the methodof B. C. Anderson. J. Org. Chem. 27. 2720(1962) using methallylchloride. Z-methylbutenyl chloride [H. Hoberg, Annalen der Chemie, 656,l (1962)] and 2-methylpent-2-enyl chloride [M. B. Evans et al., J. Chem.Soc., 5045 1962)] as starting materials for the l-methyl-l-ethyl andl-propylcyclopropyl bromides,

respectively.

EXAMPLE 293 A mixture of S-ethyl-l ,4,5,6,6a,l0,11,15b-octahydro-3l-l-benzo[6,7]cyclohepta[ l,2,3-de]pyrido[2, la]isoquinolin-S-ol (lsomer A) (1.5g), described in Example 189 andanhydrous sodium acetate (0.6g) in acetic anhydride is heated at 130Cfor 16 hrs. The reaction mixture is cooled, diluted with benzene andwater. The benzene layer is separated, washed with sodium carbonatesolution and water and then dried over magnesium sulfate. Concentrationof the benzene extract afford 5-ethyl-1,4,5,6,6a,l0,l 1 ,15b-octahydro-3H-benzo[ 6,7 ]cyclohepta[ l,2,3-de]pyrido-2, l a]isoquinolin-S-olacetate as an oil. 'y a 1735 cm. The corresponding hydrochloric acidaddition salt has m.p. 238-240C after recrystallization fromisopropanol-ether.

The procedure of Example 293 may be followed to prepare other acrylatedderivatives of formula I in which Alk is organic radical D in which L islower alkanoyloxy. In each case, the amounts of the appropriateS-substituted-l ,4,5,6,6a,10,1 1,15b-octahydro-3H- benzo[6,7]cyclohepta[ l ,2,3-de-]pyrido[2, 1 -a]- isoquinolin-S-ol, forinstance those prepared in Examples 189-292, and the acyl anhydride areequivalent to the amounts of 5-ethyl-1,4,5,6,6a,l0,l1,15b-octahydro-3H-benzo[6,7]cyclohepta[ l,2,3-de]pyrido[2,la]isoquinolin-5-ol and acetic anhydride used inExample 293. For example, 5-ethy1-l,4,5,6,6a,10.11,15boctahydro-3H-benz[6 ,7] cyclohepta[l ,2,3-de]- pyrido[2,1-a]isoquinolin--olheptanoate, 'y f 1731 cm, may be obtained by replacing acetic anhydridewith an equivalent amount of heptanoic anhydride in the procedure ofExample 293. Again, for example,5-t-butyl-l,4,5,6,6a,10,l1,15b-octahydro-3H- benzo[6,7]cyclohepta[ l,2,3-de]pyrido[2, l a]isoquinolin-S-ol acetate (lsomer A), nmr(CDCl2.l2(s,3H)4.86(t,ll-l), may be obtained by replacing S-ethyl-l,4,5,6,6a, 10,1 1,15b-octahydro-3H-benzo[6,7]cyclohepta[1,2,3-de]pyrido[2,l-a]isoquinolin- 5-01 with an equivalent amount of thecorresponding S-t-butyl analog (lsomer A), prepared as described inExample 190, in the procedure of Example 293. The hydrochloric acidaddition salt of S-t-butyl- 1,4,5,6,6a, l 0,11,15b-octahydro-3H-benzo[6,7]cycl0hepta[1,2,3-de]pyrido[2,l-a]isoquinolin-5-oltate (lsomer A) has m.p. 228229C.

EXAMPLE 294 A solution of 1,3,4,6,6a,10,l1,15b-octahydro-5H-benzo[6,7]cyclohepta[1,2,3-de]pyrido[2,1- a]isoquinolin-S-one (3.0 g),described in Example 171 in 50 ml of acetic acid, 3.0 ml ofethanedithiol and 3.0 ml of boron trifluoride etherate is left at roomtemperature for 18 hours and then poured on water and extracted withether. The organic phase is washed to neutral with a saturated solutionof sodium carbonate, dried with magnesium sulfate and concentrated todryness. The residue is triturated with ether and the solid collectedyielding l,3,4,6,6a-l0,l 1,15b-octahydro-5H- benzo[6,7]cyclohepta[l,2,3-de]pyrido[ 2, l a]isoquinolin-S-one dithioketal, m.p. 220-225C.

If desired this product may be separated into its A and B isomers bychromatography on silica gel. The corresponding lsomer B has m.p. afterelution with chloroform and recrystallization from methanolhexane andthe corresponding lsomer A, has m.p.

ace-

ethylene 225-230C after elution with methanol and recrystallization frommethanol-hexane.

The procedure of Example 294 may be followed to prepare thecorresponding ethylene dithioketals of the other aminoketones of ketonesof formula VIII of this invention, listed in Examples 172- l 88. In eachcase the appropriate aminoketone is used as starting material instead of1,3 ,4,6,6a, 1 0,1 1,15b-octahydro-5H-benzol 6,7 ]cyclohepta[l,2.3-de]pyrido[2, l -a]isoquinolin- -one.

EXAMPLE 295 To a boiling solution of 1 ,3,4,6,6a,10,11,15b-octahydro-5I-I-benzo[6,7]cycloheptal l ,2,3-de ]pyrido[2, la]isoquinolin-S-one ethylene dithioketal (17.0 g), described in Example294 in 1000 ml of tetrahydrofuran, Raney nickel (170 g) is addedportionwise and the reaction mixture is refluxed for six hours. Afterdecanting and concentrating to a minimum volume, it is poured on waterand extracted with ether, dried and concentrated to an oil. This oil isdissolved in ether and treated with gaseous hydrochloric acid. Theresulting precipitate is recrystallized from isopropanol-acetone toyield a product identical withl,4,5,6,6a-10,l1,15b-octahydro-3H-benzo[6,7]cyclohepta[1,2,3-de]pyrido[2,la]isoquinoline(Isomer A) hydrochloride described in Example 85.

The procedure of Example 295 may be followed to prepare otherbenzocycloheptaisoquinolines of formula I listed in Table XI. In eachcase an equivalent amount of the appropriate thioketal of theaminoketones listed in Table VII, prepared according to the proceduredescribed in Example 294, is used as the thioketal starting materialinstead of 1,3,4,6,6a- 10,1 1 ,15b-octahydro-5H-benzo[6,7]-cyclohep- 38chloric acid addition salt of this free base has m.p. 290295C.

The corresponding acetic acid ester is prepared by reacting the abovealcohol with acetic anhydride in presence of pyridine. The resulting5-acetoxy- 1,4,5,6,6a,l0,11,15b-octahydro-3H-benzo[6,7]-cyclohepta[1,2,3-de]pyrido[2,l-a]isoquinoline is characterized by itsnmr spectrum showing a CH CO chemical shift at 2.l8(CDCl Itshydrochloride salts melts at 265-270C.

Using the isomer B of l,3,4,6,6a,10,11,15b-octahydro-5H-benzo[6,7]cyclohepta[ 1 ,2,3-de ]pyrido[ 2,1- a]isoquinolin-5-one described inExample 171, the corresponding alcohol B, m.p. l37-140 is isolated. Thehydrochloric acid addition salt of this free base melts at 280285C.

These free bases maybe converted to their corresponding tosylates ormesylates and reduced with lithium aluminum hydride or sodium amalgam,according to the methods described by Fieser and Fieser, cited above,pp. 292-294, see also 0. H. Wheeler in The Chemistry of the CarbonylGroup, cited above, to give a compound identical to1,4,5,6,6a,10,l1,15b-octahydro[l,2,3-de]pyrido[2,l-a]isoquinoline(isomer A or isomer B, respectively) described in Example 85.

The procedure of Example 313 may be followed to prepare the productslisted in Table XI, for example, the product of Example 31 1. In eachcase the appropriate starting material, an aminoketone product listed inta[1,2,3-de]pyrido[2,1-a]isoquinolin-5-one ethylene dithioketal,

TABLE XI EXAMPLE STARTING MATERIAL PRODUCT [(PREFIX LISTED BELOW)-l,3,4,6,6a,l0,l 1,15b- OCTAHYDRO-5H-BENZO[6,7]- CYCLOHEPTA[1,2,3-de]-PYRIDO[2,l-a]ISOQUINOLlN- ISOQUINOLINE EXAMPLE 313 To a suspension of1,3,4,6,6a,10,11,15b-octahydro-5H-benzo[6,7]cyclohepta[1,2,3-de]pyrido[2,1- a]isoquinolin-S-one isomerA (2.0 g), described in Example 171, in ml of methanol, sodiumborohydride (2.5 g) is added portionwise. The mixture is heated underrefluxing conditions for 1 hour. After removal of the methanol undervacuum, water is added and the mixture is extracted with ethyl acetate.The extract is dried, concentrated to dryness. The residue iscrystallized from ether-hexane to afford the free base, 1,4,5,6,6a,10,11,15b-octahydro-3H-benzo[6,7]cyclohepta[1,2,3-de]pyrido[2,1-a]isoquinolin-5-ol,isomer A m.p. 157159C. The corresponding hydro- Table VII, for example,the product of Example 187, is reduced to the corresponding 5-alcohol,for example, 4-sec-butyl-1,4,5,6,6a,l0,l1,15b-octahydro-3H-benzo[6,7]cyclohepta[1,2,3-de]pyrido[2,1-a]isoquinolin-5-ol[nmr 8 (CDCl )4.52(d,1I-I); the corresponding hydrochloric acidaddition salt has m.p. 272280C.], converted to its correspondingtosylate or mesylate, and reduced again according to the aboveprocedure.

The procedure of the first part of Example 313 may be followed toprepare other 5.-alcohols listed in Table XII, instead of1,4,5,6,6a,10,11,15b-octahydro-3H-benzo[6,7]cyclohepta[1,2,3-de]pyrido[2,1- a]isoquinolin-S-ol. In eachcase an equivalent amount of appropriate starting material, anaminoketone product listed in Table VII is reduced with sodium borohy-

1. A PHARMACEUTICAL COMPOSITION HAVING CENTRAL NERVOUS SYSTEM ACTIVITYCONTAINING A CARRIER AND AN AMOUNT UP TO ABOUT 500 MILLIGRAMS EFFECTIVETO PRODUCE A CENTRAL NERVOUS SYSTEM DEPRESENT EFFECT IN A MAMMAL WITHOUTDELETERIOUS SIDE-EFFECTS OF A COMPOUND SELECTED FROM THE GROUPCONSISTING OF5-T-BBUTYL1,4,5,6,6A,10,11,15B-OCTAHYDRO-3H-BENZO(6,7)CYCLOHEPTA(1,2,3-DE)PYRIDO(2,1-A)ISOQUINOLIN-5-OL;5-ISOPROYL1,4,5,6,6A,10,11,15B-OCTAHYDRO-3H-BENZO(6,7)CYCLOHEPTA(1,2,3-DE)PYRIDO(2,1-A)ISOQUINOLIN-5-OL;5-CYCLOHEXYL1,4,5,6,6A,10,11,15B-OCTAHYDRO-3H-BENZO(6,7)CYCLOHEPTA(1,2,3-DE)PYRIDO(2,1-A)ISOQUINOLIN-5-OL, AND5-PHENYL1,4,5,6,6A,10,11,15B-OCTAHYDRO-3H-BENZO(6,7)CYCLOHEPTA(1,2,3,-DE)PYRIDO(2,1-A)ISOQUINOLIN-5-OL.
 2. The composition of claim 1 whereinsaid compound is5-t-butyl-1,4,5,6,6a,10,11,15b-octahydro-3H-benzo(6,7)cyclohepta(1,2,3-de)pyrido(2,1-a)isoquinolin-5-ol.
 3. The composition of claim 1wherein said compound is5-isoproyl-1,4,5,6,6a,10,11,15b-octahydro-3H-benzo(6,7)cyclohepta(1,2,3-de)pyrido(2,1-a)isoquinolin-5ol.
 4. The compositionof claim 1 wherein said compound is5-cyclohexyl-1,4,5,6,6a,10,11,15b-octahydro-3H-benzo(6,7)cyclohepta(1,2,3-de)pyrido(2,1-a)isoquinolin-5-ol.
 5. The compositionof claim 1 wherein said compound is5-phenyl-1,4,5,6,6a,10,11,15b-octahydro-3H-benzo(6,7)cyclohepta(1,2,3-de)pyrido(2,1-a)isoquinolin-5-ol.
 6. A method of producing centralnervous system depressant effect in a mammal which comprisesadministering to a mammal an amount up to 500 milligrams per kilogram ofmammal weight per day effective to produce a central nervous systemdepressant effect in a mammal without deleterious side-effects of acompound selected from the group consisting of5-t-butyl-1,4,5,6,6a,10,11,15b-octahydro-3H-benzo(6,7)cyclohepta(1,2,3,-de)pyrido(2,1-a)isoquinolin-5-ol; 5-isoproyl-1,4,5,6,6a,10,11,15b-octahydro-3H-benzo(6,7)cyclohepta(1,2,3,de)pyrido(2,1-a)isoquinolin-5-ol;5-cyclohexyl-1,4,5,6,6a,10,11,15b-octahydro-3H-benzo(6,7)cyclohepta(1,2,3-de)pyrido(2,1-a)isoquinolin-5-ol, and5-phenyl-1,4,5,6,6a,10,11,15b-octahydro-3H-benzo(6,7) cyclohepta(1,2,3-de)pyrido(2,1-a)isoquinolin-5-ol.
 7. The method of claim 6 whereinsaid compound is 5-t-butyl-1,4,5,6,6a,10,11,15b-octahydro-3H-benzo(6,7)cyclohepta(1,2,3-de)pyrido(2,1-a)isoquinolin-5-ol.
 8. The method of claim 6 wherein said compound is5-isoproyl-1,4,5,6,6a,10,11,15b-octahydro-3H-benzo(6,7)cyclohepta(1,2,3-de)pyrido(2,1-a)isoquinolin-5-ol.
 9. The method of claim 6 wherein said compound is5-cyclohexyl-1,4,5,6,6a,10,11,15b-octahydro-3H-benzo(6,7)cyclohepta(1,2,3-de)pyrido(2,1-a)isoquinolin-5-ol.
 10. The method of claim 6 whereinsaid compound is 5-phenyl-1,4,5,6,a,10,11,15b-octahydro-3H-benzo(6,7)cyclohepta(-de)1,2,3-depyrido(2,1-a)isoquinolin-5-ol.